BRPI0608549A2 - inibidores da enzima histona deacetilase à base de n-hidroxiamidas (omega)-substituìdas por grupos tricìclicos - Google Patents

inibidores da enzima histona deacetilase à base de n-hidroxiamidas (omega)-substituìdas por grupos tricìclicos Download PDF

Info

Publication number
BRPI0608549A2
BRPI0608549A2 BRPI0608549-0A BRPI0608549A BRPI0608549A2 BR PI0608549 A2 BRPI0608549 A2 BR PI0608549A2 BR PI0608549 A BRPI0608549 A BR PI0608549A BR PI0608549 A2 BRPI0608549 A2 BR PI0608549A2
Authority
BR
Brazil
Prior art keywords
group
dibenzo
hexanoic acid
dihydro
hydroxyamide
Prior art date
Application number
BRPI0608549-0A
Other languages
English (en)
Portuguese (pt)
Inventor
Tula Dimoulas
Antonio Guidi
Danilo Giannotti
Nicholas Harmat
Original Assignee
Menarini Int Operations Lu Sa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Menarini Int Operations Lu Sa filed Critical Menarini Int Operations Lu Sa
Publication of BRPI0608549A2 publication Critical patent/BRPI0608549A2/pt

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D243/00Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38[b, e]- or [b, f]-condensed with six-membered rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D267/00Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02Seven-membered rings
    • C07D267/08Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/16Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D267/20[b, f]-condensed
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D281/00Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02Seven-membered rings
    • C07D281/04Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/16[b, f]-condensed
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D285/00Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/36Seven-membered rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D291/00Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/08Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/02Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Oncology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
BRPI0608549-0A 2005-03-15 2006-03-13 inibidores da enzima histona deacetilase à base de n-hidroxiamidas (omega)-substituìdas por grupos tricìclicos BRPI0608549A2 (pt)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000042 IT1362675B (it) 2005-03-15 2005-03-15 N-idrossiammidi -sostituiti con gruppi triciclici come inibitori dell'istone deacelitasi,loro preparazione ed impiego in formulazioni farmaceutiche
PCT/EP2006/060661 WO2006097449A1 (en) 2005-03-15 2006-03-13 N-hydroxyamides omega-substituted with tricyclic groups as histone deacetylase inhibitors, their preparation and use in pharmaceutical formulations

Publications (1)

Publication Number Publication Date
BRPI0608549A2 true BRPI0608549A2 (pt) 2010-01-12

Family

ID=36676439

Family Applications (1)

Application Number Title Priority Date Filing Date
BRPI0608549-0A BRPI0608549A2 (pt) 2005-03-15 2006-03-13 inibidores da enzima histona deacetilase à base de n-hidroxiamidas (omega)-substituìdas por grupos tricìclicos

Country Status (22)

Country Link
US (1) US20080275023A1 (ar)
EP (1) EP1863776A1 (ar)
JP (1) JP2008533088A (ar)
KR (1) KR20080003336A (ar)
CN (1) CN101142197A (ar)
AP (1) AP2007004170A0 (ar)
AR (1) AR053171A1 (ar)
AU (1) AU2006222883A1 (ar)
BR (1) BRPI0608549A2 (ar)
CA (1) CA2600521A1 (ar)
CO (1) CO6321131A2 (ar)
EA (1) EA013015B1 (ar)
IL (1) IL185879A0 (ar)
IT (1) IT1362675B (ar)
MA (1) MA29673B1 (ar)
MX (1) MX2007011071A (ar)
NI (1) NI200700222A (ar)
NO (1) NO20075229L (ar)
SA (1) SA06270133B1 (ar)
TW (1) TW200719900A (ar)
WO (1) WO2006097449A1 (ar)
ZA (1) ZA200708754B (ar)

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0523040D0 (en) * 2005-11-11 2005-12-21 Cyclacel Ltd Combination
AU2007313818B2 (en) * 2006-10-28 2013-02-14 Forum Pharmaceuticals Inc. Inhibitors of histone deacetylase
AU2013205135B2 (en) * 2006-10-28 2015-11-05 Forum Pharmaceuticals Inc. Inhibitors of histone deacetylase
AU2007332867B2 (en) * 2006-12-11 2012-02-16 Merck Sharp & Dohme Corp. Substituted diazepine sulfonamides as bombesin receptor subtype-3 modulators
JP2011102240A (ja) * 2008-02-29 2011-05-26 Univ Of Tokyo 三環性化合物
US8202989B2 (en) 2009-01-12 2012-06-19 Council Of Scientific And Industrial Research One step process for the preparation of substituted 5, 10-dihydrodibenzo [b,e][1, 4]diazepine-11-ones
JP2013525308A (ja) * 2010-04-16 2013-06-20 キュリス,インコーポレイテッド K−ras変異を有する癌の治療
WO2012045194A1 (en) * 2010-10-09 2012-04-12 Abbott Laboratories Benzodiazepinones as fak inhibitors for treatment of cancer
RU2519546C1 (ru) * 2013-01-16 2014-06-10 Общество С Ограниченной Ответственностью "Биоинтегратор" (Ооо "Биоинтегратор") КОНЪЮГАТЫ И МАЛЫЕ МОЛЕКУЛЫ, ВЗАИМОДЕЙСТВУЮЩИЕ С РЕЦЕПТОРОМ CD16а
AU2014219042A1 (en) 2013-02-19 2015-09-17 Icahn School Of Medicine At Mount Sinai Tricyclic heterocycles as anticancer agents
EP3116857B1 (en) 2014-03-11 2019-02-06 Icahn School of Medicine at Mount Sinai Constrained tricyclic sulfonamides
CN106458936A (zh) 2014-03-11 2017-02-22 西奈山伊坎医学院 作为抗癌药的三环‑2‑氨基环烷醇衍生的磺酰胺
CA2968464A1 (en) 2014-11-25 2016-06-02 Bayer Pharma Aktiengesellschaft Substituted pyridobenzodiazepinone-derivatives and use thereof
EP3226689B1 (en) 2014-12-05 2020-01-15 Merck Sharp & Dohme Corp. Novel tricyclic compounds as inhibitors of mutant idh enzymes
WO2016089833A1 (en) 2014-12-05 2016-06-09 Merck Sharp & Dohme Corp. Novel tricyclic compounds as inhibitors of mutant idh enzymes
US10442819B2 (en) 2014-12-05 2019-10-15 Merck Sharp & Dohme Corp. Tricyclic compounds as inhibitors of mutant IDH enzymes
GB201510010D0 (en) 2015-06-09 2015-07-22 King S College London PDD and BPD compounds
GB201514928D0 (en) 2015-08-21 2015-10-07 King S College London PDD compounds
US20180339985A1 (en) 2015-08-21 2018-11-29 Femtogenix Limited Pdd compounds
WO2017044571A1 (en) * 2015-09-09 2017-03-16 Icahn School Of Medicine At Mount Sinai Tricyclic sultam sulfonamides as anticancer and neuroprotective agents
JP6955485B2 (ja) 2015-09-09 2021-10-27 アイカーン スクール オブ メディスン アット マウント サイナイIcahn School of Medicine at Mt. Sinai 抗がん剤としての複素環式の限定された三環系スルホンアミド
CN108349943A (zh) 2015-09-09 2018-07-31 西奈山伊坎医学院 杂环受限三环磺酰胺作为抗癌试剂
CN105806973B (zh) * 2016-03-10 2019-01-18 中国医学科学院肿瘤医院 Uplc-ms/ms法测定人血浆中莎巴比星及其代谢产物m3的血药浓度
CN112041307B (zh) 2018-02-06 2024-02-09 伊利诺伊大学评议会 作为选择性雌激素受体降解剂的取代的苯并噻吩类似物
KR102301274B1 (ko) * 2019-08-05 2021-09-14 리퓨어생명과학 주식회사 히스톤 아세틸트렌스퍼라제 p300 억제용 신규 화합물 및 이를 포함하는 항섬유화 조성물
KR102243465B1 (ko) * 2019-08-05 2021-04-22 리퓨어생명과학 주식회사 히스톤 아세틸트렌스퍼라제 p300 억제용 신규 화합물 및 이를 포함하는 항섬유화 조성물
WO2023020416A1 (zh) * 2021-08-16 2023-02-23 勤浩医药(苏州)有限公司 三环化合物、包含其的药物组合物及其用途

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS53121780A (en) * 1977-04-01 1978-10-24 Teikoku Hormone Mfg Co Ltd Dibenzazepin derivatives and process for their preparation
JPS6033110B2 (ja) * 1977-09-12 1985-08-01 帝国臓器製薬株式会社 ジベンズアゼピン誘導体
AR035455A1 (es) * 2001-04-23 2004-05-26 Hoffmann La Roche Derivados triciclicos de alquilhidroxamato , procesos para su elaboracion, composiciones farmaceuticas que los contienen, y el uso de dichos compuestos en la preparacion de medicamentos
CA2511493A1 (en) * 2002-12-25 2004-07-15 Daiichi Pharmaceutical Co., Ltd. Diamine derivatives

Also Published As

Publication number Publication date
CO6321131A2 (es) 2011-09-20
ZA200708754B (en) 2008-10-29
IT1362675B (it) 2009-06-25
MX2007011071A (es) 2007-10-08
NO20075229L (no) 2007-11-08
TW200719900A (en) 2007-06-01
AR053171A1 (es) 2007-04-25
ITFI20050042A1 (it) 2006-09-16
AP2007004170A0 (en) 2007-10-31
JP2008533088A (ja) 2008-08-21
KR20080003336A (ko) 2008-01-07
AU2006222883A1 (en) 2006-09-21
CA2600521A1 (en) 2006-09-21
SA06270133B1 (ar) 2009-05-16
CN101142197A (zh) 2008-03-12
EA200701969A1 (ru) 2008-02-28
WO2006097449A1 (en) 2006-09-21
EP1863776A1 (en) 2007-12-12
US20080275023A1 (en) 2008-11-06
IL185879A0 (en) 2008-01-06
MA29673B1 (fr) 2008-08-01
EA013015B1 (ru) 2010-02-26
NI200700222A (es) 2008-07-24

Similar Documents

Publication Publication Date Title
BRPI0608549A2 (pt) inibidores da enzima histona deacetilase à base de n-hidroxiamidas (omega)-substituìdas por grupos tricìclicos
CN110088099B (zh) 作为ehmt2抑制剂的胺取代的杂环化合物及其使用方法
JP6951767B2 (ja) 抗癌薬として使用される複素環式化合物
ES2815681T3 (es) Ureas cíclicas como inhibidores de ROCK
DK2152258T3 (en) Derivatives of fluorene, anthracene, xanthene, acridine dibenzosuberone AND DERIVATIVES AND USES
JP7425724B2 (ja) Ehmt2阻害剤としてのアミン置換複素環化合物及びその誘導体
WO2016126722A1 (en) 3-alkyl bicyclic [4,5,0] hydroxamic acids as hdac inhibitors
CN105518005A (zh) 作为rock抑制剂的三环吡啶-甲酰胺衍生物
PT1746097E (pt) Heterociclos fundidos de 1,4-di-hidropiridina, processo para a sua preparação, utilização e composições que os contêm
BR112012002251B1 (pt) processo para a fabricação do composto de fórmula (1), compostos, composição, método analítico e processo para a fabricação do composto (i)
PT1913004E (pt) 8-metoxi-9h-isotiazolo[5,4-b]quinolina-3,4-dionas e compostos relacionados como agentes anti-infecciosos
ES2659337T3 (es) Derivados de quinazolina y su uso como inhibidores de ADN metiltransferasa
BRPI0619422A2 (pt) derivados de cromona úteis como antagonistas de receptores vr1
FR2941948A1 (fr) Derives d'azaindoles en tant qu'inhibiteur des proteines kinases abl et src
KR20150119390A (ko) 항암제로서의 삼환식 헤테로사이클
RU2721120C2 (ru) Новые гетероциклические соединения как ингибиторы brd4
BR112017016819B1 (pt) Compostos de diaza-benzofluorantreno
Yoshiizumi et al. Synthesis and structure–Activity relationships of 5, 6, 7, 8-Tetrahydropyrido [3, 4-b] pyrazine-based hydroxamic acids as HB-EGF shedding inhibitors
CA2730071A1 (fr) Derives anticancereux, leur preparation et leur application en therapeutique
ES2663498T3 (es) Tetrahidro-tetrazolo[1,5-a]pirazinas como inhibidores de ROR-gamma
JP2006522012A (ja) ベンゾキサゾシンおよびそのモノアミン再吸収阻害剤としての用途
MXPA05007977A (es) Nuevos compuestos de azepina triciclica, un proceso para su preparacion y composiciones farmaceuticas que los contienen.
AU2022307943A1 (en) Inhibitors of alpha-hemolysin of staphylococcus aureus
AU2022221336A1 (en) OXADIAZOLYL DIHYDROPYRANO[2,3-b]PYRIDINE INHIBITORS OF HIPK2 FOR TREATING KIDNEY FIBROSIS
PT1486503E (pt) Derivados de benzotiazina e de benzotiadiazina, processo para a sua preparação e as composições farmacêutica que os contêm

Legal Events

Date Code Title Description
B08F Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]

Free format text: REFERENTE AS 5A E 6A ANUIDADES.

B08K Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette]

Free format text: REFERENTE AO DESPACHO 8.6 PUBLICADO NA RPI 2161 DE 05/06/2012.